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The Difference in Cytotoxic Activity Between Two Optical Isomers Of molecules Communication The Difference in Cytotoxic Activity between Two Optical Isomers of Gelsemine from Gelsemium elegans Benth. on PC12 Cells Li Lin 1, Yan-Chun Liu 1,2 and Zhao-Ying Liu 1,2,* 1 College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; [email protected] (L.L.); [email protected] (Y.-C.L.) 2 Hunan Engineering Technology Research Center of Veterinary Drugs, Hunan Agricultural University, Changsha 410128, China * Correspondence: [email protected]; Tel.: +86-151-1117-9464 Academic Editors: Francesco Epifano and Serena Fiorito Received: 2 May 2019; Accepted: 22 May 2019; Published: 25 May 2019 Abstract: Two optical isomers, +/ gelsemine (1, 2), together with one known compound were isolated − from the whole plant of G. elegans. The structures of the separated constituents were elucidated on 1D and 2D (1H-1H COSY, HMBC, HSQC) NMR spectroscopy and high-resolution mass spectrometry (HRMS). The isolated alkaloids were tested in vitro for cytotoxic potential against PC12 cells by the MTT assay. As a result, (+) gelsemine (compound 1) exhibited cytotoxic activity against PC12 cells with an IC value of 31.59 µM, while ( ) gelsemine (compound 2) was not cytotoxic. 50 − Keywords: Gelsemium elegans; gelsemine; koumine; PC12 cells 1. Introduction Gelsemium elegans Benth. (G. elegans), referred to as “Gou-Wen” and “Duan-Chang-Cao” in China, belongs to Loganiaceae family and is a famous toxic plant that is widely distributed in Southeast Asia and southern China [1]. This plant has been used as a traditional medicine for the treatment of pain, spasticity, skin ulcers, migraines, neuralgia, sciatica, cancer, and various types of sores [2–8]. The Gelsemium genus includes three species, all of which have a large number of alkaloids, including indole, bisindole, and monoterpenoid alkaloids [7,9–11]. To date, more than 120 kinds of alkaloids, including some stereo-isomer compounds, have been isolated from G. elegans. Most of the alkaloids are classified into five types based on their chemical structure characteristics: gelsedine-, koumine-, humantenine-, sarpagine-, and gelsemine-type [5,12]. The Gelsemium alkaloids have potent cytotoxic, analgestic, anti-inflammatory, immunomodulating, and antiarrhythmic activities, which means they have potential as new drugs [7,13]. Their tremendous effects and the unusual and densely functionalized nature of the hexacyclic structure have been used in the development of synthetic approaches toward gelsemine, humantenine, and gelsedine-type alkaloids. The first total syntheses of ( )-gelsemine were ± disclosed in 1994 by the groups of Johnson. Gelsemine and koumine of G. elegans inhibited Tetrahymena thermophila cells’ growth in a dose-dependent manner [14,15]. In the present study, two optical isomers, +/ gelsemine (1, 2), together with one known compound, koumine, were isolated from the whole − plant of G. elegans (Figure1). According to the structure of gelsemine, gelsemine has seven chiral carbon and two chiral nitrogen atoms. The structures of these compounds were elucidated mainly by NMR spectroscopic and high resolution mass spectroscopic methods. Furthermore, all compounds have been tested in vitro for cytotoxic potential against PC12 cells by MTT assay. Molecules 2019, 24, 2004; doi:10.3390/molecules24102004 www.mdpi.com/journal/molecules Molecules 2019, 24, x 2 of 6 Molecules 2019, 24, 2004 2 of 6 2. Results and Discussion Molecules 2019, 24, x 2 of 6 2. Results and Discussion Figure 1. The structures of compound ((±)-gelsemine)-gelsemine ( 1//2) and koumine ( 3). ± 2. Results and Discussion 1 13 Compound 1 wasFigure isolated 1. The structuresas a white of powdercompound (for (±)-gelsemine H and C-NMR,(1/2) and koumine see Table (3). 1). The molecular formulaCompound was determined1 was isolated as C20H as23N a white2O2 bypowder HR-ESI-MS (for 1inH positive and 13C-NMR, mode (m/z see 323.1758 Table1). The[M + molecular H]+, calcd + 1 13 1 13 + formulafor [M +Compound wasH] 323.1751). determined 1 was The isolated as H C 20andH as23 NaC-NMR white2O2 by powder (See HR-ESI-MS supplementary (for H inand positive C-NMR, material mode sees (FigureTablem/z 323.1758 1). S1–S6) The molecular [Mprofile+ H] of , calcdcompoundformula for [M 1was +matchedH] determined+ 323.1751). with asthe C Thereported20H231NH2O and 2data by 13HR-ESI-MS forC-NMR gelsemine (See in positive supplementary[16]. mode (m/z materials 323.1758 [M Figures + H]+, S1–S6)calcd + 1 13 profileforCompound [M ofcompound + H] 323.1751). 2 was1 matchedisolated The H as with and a yellow theC-NMR reported powder (See data supplementaryand for had gelsemine similar material NMR [16]. datas Figure to 1 S1–S6)(Table profile1), but ofthe puritycompoundCompound of compound 1 matched2 was 2 isolatedwas with lower the as reported athan yellow 1. Thedata powder molecularfor gelsemine and had formula [16]. similar was NMR determined data to 1 as(Table C20H123),N but2O2 the by Compound 2 was isolated as a yellow powder+ and had similar NMR+ data to 1 (Table 1), but the purityHR-ESI-MS of compound in positive2 was mode lower (m/z than 323.17631. The [M molecular + H] , calcd formula for [M was + H] determined 323.1751). asThe C 20retentionH23N2O time2 by purity of compound 2 was lower than 1. The molecular formula was determined2 as C20H23N2O2 by HR-ESI-MSof compound in 1 positive and 2 was mode 16.861 (m/z min323.1763 and 16.619 [M + H] min,+, calcd respectively. for [M + H]The+ 323.1751).MS spectra The of retentioncompounds time 1 HR-ESI-MS in positive mode (m/z 323.1763 [M + H]+, calcd for [M + H]+ 323.1751). The retention time ofand compound 2 are shown1 and in Figure2 was 16.8612. The minproduct and 16.619ions of min, compounds respectively. 1 and The 2 were MS2 quitespectra similar. of compounds According1 of compound 1 and 2 was 16.861 min and 16.619 min, respectively. The MS2 spectra of compounds 1 andto the2 are data shown of 1H in and Figure 13C-NMR(See2. The product supplementary ions of compounds material1 ands Figure2 were S7–S12), quite similar. compound According 2 was to and 2 are shown in Figure 2. The product ions of compounds 1 and 2 were quite similar. According theidentified data of as1H gelsemine. and 13C-NMR(See supplementary materials Figures S7–S12), compound 2 was identified to the data of 1H and 13C-NMR(See supplementary materials Figure S7–S12), compound 2 was as gelsemine.identified as gelsemine. (a) (a) (b(b) ) Figure 2. The MS/MS spectra of compound 1 (a) and 2 (b). FigureFigure 2. 2.The The MS MS/MS/MS spectra spectra of of compound compound 11 ((aa)) andand 2 (b). Molecules 2019, 24, 2004 3 of 6 Compound 3 was isolated as a yellow powder with the following properties: positive ESI-MS m/z: 307.1812 [M + H]+, 13C-NMR (See supplementary materials Figure S13) (101 MHz, MeOD) δ 187.85 (2-C), 155.04 (13-C), 144.59 (8-C), 137.95 (19-C), 129.51 (11-C), 127.72 (10-C), 124.58 (9-C), 121.47 (12-C), 116.93 (18-C), 71.88 (3-C), 61.91 (17-C), 58.97 (7-C), 58.15 (21-C), 57.77 (5-C), 46.59 (20-C), 42.84 (N-Me), 38.52 (16-C), 33.97 (15-C), 30.46 (6-C), 25.93 (14-C). 1H-NMR(See supplementary materials Figure S14) (400 MHz, MeOD) δ 7.65 (1H, d, J = 7.3 Hz, 12-H), 7.55 (1H, d, J = 7.6 Hz, 9-H), 7.40 (1H, td, J = 7.6, 1.2 Hz, 11-H), 7.33 (1H, td, J = 7.5, 1.0 Hz, 10-H), 4.92 (1H, dd, J = 8.3, 1.7 Hz, 18α-H), 4.82 (dd, J = 11.2, 0.8 Hz, 1H, 18β-H), 4.69 (1H, dd, J = 17.6, 11.3 Hz, 19-H), 4.32 (1H, dd, J = 12.0, 4.6 Hz, 17α-H), 3.64 (1H, d, J = 12.0 Hz, 17β-H), 3.29 (1H, d, J = 11.9 Hz, 21α-H), 3.03 (1H, m, 21β-H), 2.88 (1H, m, 5-H), 2.67 (1H, s, N-Me), 2.42 (2H, m, 6-H), 1.87 (dt, J = 14.8, 2.0 Hz, 1H, 14β-H). This profile was consistent with the reported NMR data for koumine [16]. Table 1. 1H-NMR (400 MHz) and 13C-NMR (100 MHz) data for Compound 1 and 2 in MeOD (δ in ppm and J in Hz). Compound 1 Compound 2 Position δC δH δC δH 2 179.26 / 180.56 / 3 69.58 3.60 (1H, s) 70.97 3.64 (1H, s) 5 71.81 4.12 (1H, d, 11.0) 73.28 4.13 (1H, d, 11.0) 6 50.63 1.99 (1H, s) 51.93 2.01 (1H, s) 7 54.19 / 55.55 / 8 131.70 / 133.00 / 9 127.99 7.46 (1H, d, 7.6) 129.30 7.46 (1H, d, 7.6) 10 121.23 7.00 (1H, t, 7.6) 122.65 7.00 (1H, t, 7.6) 11 128.10 7.22 (1H, t, 7.7) 129.49 7.22 (1H, t, 7.7) 12 108.97 6.87 (1H, d, 7.7) 110.40 6.87 (1H, d, 7.7) 13 141.20 / 142.60 / 2.04 (1H, m) 2.04 (1H, m) 14 22.34 23.70 2.84 (1H, dd, 14.3, 2.1) 2.84 (1H, m) 15 35.63 2.34 (1H, t) 36.98 2.38 (1H, s) 16 37.50 2.49 (1H, m) 38.97 2.50 (1H, m) 3.97 (1H, d, 11.0) 3.97 (1H, m) 17 60.81 62.14 3.72 (1H, s) 3.72 (1H, s) 4.98 (1H, d, 17.8) 4.98 (1H, d, 17.8) 18 111.59 113.16 5.05 (1H, d, 11.0) 5.06 (1H, d, 11.0) 6.25 (1H, dd,17.8, 19 138.31 6.26 (1H, dd, 17.8,11.0) 139.48 11.0) 20 53.68 / 55.02 / 2.78 (1H, d,10.8) 2.80 (1H, d, 10.7) 21 65.17 66.45 3.33 (1H, d, 1.3) / N-CH3 39.03 2.28 (3H,s) 40.43 2.31 (3H, s) The effects of the three compounds on the activity of poorly differentiated PC-12 cells and highly differentiated PC-12 cells (Figure3) were investigated, and it was found that only compound 1 inhibited viability in highly differentiated PC-12 cells, while the other compounds were not toxic to either type of PC-12 cells.
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